Injury can trigger an acute inflammatory response, even in the absence of concomitant infection. “Sterile” inflammation is also associated to several types of cancer. Two events are key for the development of sterile inflammation: the recruitment of leukocytes, especially neutrophils and monocytes, and their activation to release proinflammatory cytokines.
High Mobility Group Box 1 (HMGB1) is a nuclear protein that signals tissue damage when released into the extracellular medium, and thus works as a Damage Associated Molecular Pattern (DAMP) (1). Extracellular HMGB1 can act both as a chemoattractant for leukocytes and as a proinflammatory mediator to induce both recruited leukocytes and resident immune cells to release TNF, IL-1, IL-6 and other cytokines Notably, immune cells secrete HMGB1 when activated by infection or tissue damage (2); mesothelioma and other cancer cells secrete HMGB1 constitutively (Jube et al., 2012).
Recent studies have shown that the proinflammatory cytokine-stimulating activity of HMGB1 depends on the redox state of 3 cysteines: C23 and C45 must form a disulfide bond within the first HMG-box domain of HMGB1, BoxA, whereas the unpaired C106 within BoxB must be in the thiol state (3-5). Both terminal oxidation of these cysteines to sulfonates (CySO3−) with reactive oxygen species (ROS) and their complete reduction to thiols (CySH) abrogates the cytokine-stimulating activity.
EP 2 068 935 disclose polymer conjugates of HMGB1 and of HMGB1 variants, such polymers are resistant to proteolysis.
There is the need for HMGB1 variants that maintain chemoattractant properties but do not induce cytokine/chemokine production. Such variants may be used to promote the repair and regeneration of the tissue.